OMIA 002222-9615 : Laryngeal paralysis, RAPGEF6-related in Canis lupus familiaris

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Mapping: "Using a genome-wide association study and haplotype analyses, . . . [Hadji Rasouliha et al. (2019)] mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11."

Markers: Hadji Rasouliha et al. (2019) identified "a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36) . . . a major genetic risk factor [for this disorder, laryngeal paralysis (LP), in Miniature Bull Terriers] involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP". The authors also reported that "The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame."

Hadji Rasouliha et al. (2019) quantified the effect of the marker by calculating relative risk in a cohort of "all Miniature Bull Terriers fulfilling the inclusion criteria (n = 243). In this cohort, homozygosity for the RAPGEF6 insertion was associated with a 9.91-fold (95% CI: 5.75–17.1, p < 0.0001) increased risk for LP compared with dogs, which were homozygous wildtype or carried the insertion allele in heterozygous state. The risk in dogs carrying the insertion in heterozygous state was not significantly increased compared to dogs homozygous for the wildtype allele (RR = 1.75, 95% CI: 0.61–5.03, p = 0.30)".

Clinical features: Hadji Rasouliha et al. (2019): "Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies."

Prevalence: Hadji Rasouliha et al. (2019): " The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds".

Breed: Miniature Bull Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
RAPGEF6 Rap guanine nucleotide exchange factor (GEF) 6 Canis lupus familiaris 11 NC_006593.3 (19973784..19775874) RAPGEF6 Homologene, Ensembl, NCBI gene

Variants

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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Miniature Bull Terrier Laryngeal paralysis, RAPGEF6-related RAPGEF6 insertion, gross (>20) CanFam3.1 11 g.19,841,331ins c.1793_1794ins36 p.(Ile587ProfsTer5) Hadji Rasouliha et al. (2019): XM_846793.5:c.1793_1794insTTTTTTTTTTTTTTTTTTTTTAGCCCTTGAAATTTT; XP_851886.2:p.(Ile578ProfsTer5) 2019 31647804

Reference


2019 Hadji Rasouliha, S., Barrientos, L., Anderegg, L., Klesty, C., Lorenz, J., Chevallier, L., Jagannathan, V., Rösch, S., Leeb, T. :
A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs. PLoS Genet 15:e1008416, 2019. Pubmed reference: 31647804. DOI: 10.1371/journal.pgen.1008416.

Edit History


  • Created by Frank Nicholas on 17 Jan 2020
  • Changed by Frank Nicholas on 17 Jan 2020